🛡️Immunobiology Unit 11 – Immune Tolerance and Autoimmunity

Key Concepts

• Immune tolerance involves the immune system's ability to recognize and not react to self-antigens, preventing autoimmunity
• Central tolerance occurs in the thymus and bone marrow, where self-reactive lymphocytes are eliminated or inactivated
  • Mediated by processes such as clonal deletion, receptor editing, and anergy
• Peripheral tolerance takes place in secondary lymphoid organs and tissues, regulating self-reactive lymphocytes that escape central tolerance
  • Mechanisms include suppression by regulatory T cells (Tregs), ignorance, and apoptosis
• Autoimmunity arises when immune tolerance fails, leading to an immune response against self-antigens
• Autoimmune diseases can be organ-specific (type 1 diabetes) or systemic (systemic lupus erythematosus)
• Genetic predisposition, environmental factors, and immunological imbalances contribute to the development of autoimmunity
• Diagnosis of autoimmune diseases involves detecting autoantibodies, assessing organ function, and imaging studies
• Treatment strategies aim to suppress the immune response, manage symptoms, and prevent complications

Mechanisms of Immune Tolerance

• Clonal deletion eliminates self-reactive T and B cells during their development in the thymus and bone marrow, respectively
  • Mediated by the presentation of self-antigens by antigen-presenting cells (APCs)
  • Cells that bind strongly to self-antigens undergo apoptosis
• Receptor editing allows B cells to modify their antigen receptors, potentially changing their specificity away from self-antigens
• Anergy induces a state of unresponsiveness in self-reactive lymphocytes that escape clonal deletion
  • Occurs when cells encounter self-antigens without appropriate co-stimulatory signals
• Regulatory T cells (Tregs) suppress the activation and function of self-reactive T cells in the periphery
  • Secrete immunosuppressive cytokines (IL-10, TGF-β) and express inhibitory receptors (CTLA-4, PD-1)
• Ignorance refers to the lack of interaction between self-reactive lymphocytes and their cognate antigens due to spatial separation or low antigen concentration
• Apoptosis of self-reactive cells in the periphery is induced by the engagement of death receptors (Fas) or the withdrawal of survival factors

Types of Autoimmunity

• Organ-specific autoimmunity targets specific organs or tissues, such as the pancreas in type 1 diabetes or the thyroid in Hashimoto's thyroiditis
  • Characterized by the presence of autoantibodies and T cells specific to organ-specific antigens
• Systemic autoimmunity affects multiple organs and tissues throughout the body, as seen in systemic lupus erythematosus (SLE) and rheumatoid arthritis
  • Involves the production of autoantibodies against widely distributed antigens (nuclear components, DNA)
• Autoimmune phenomena can also occur as a result of infections, malignancies, or immunodeficiencies
  • Molecular mimicry between pathogen and self-antigens can trigger cross-reactive immune responses
• Autoinflammatory diseases, such as familial Mediterranean fever, involve innate immune dysregulation without autoantibodies or self-reactive T cells
• Polyautoimmunity refers to the presence of multiple distinct autoimmune diseases in an individual

Causes and Risk Factors

• Genetic predisposition plays a significant role in the development of autoimmunity, with multiple genes contributing to disease susceptibility
  • Human leukocyte antigen (HLA) genes are strongly associated with many autoimmune diseases
• Environmental factors can trigger autoimmunity in genetically susceptible individuals
  • Infections, particularly viral infections, can initiate or exacerbate autoimmune responses through molecular mimicry or bystander activation
  • Toxins, drugs, and other chemical agents can modify self-antigens or alter immune regulation
• Hormonal factors influence the development of autoimmunity, with many diseases being more prevalent in females
  • Estrogens can enhance humoral immunity and promote the survival of autoreactive cells
• Immunological imbalances, such as defects in regulatory T cell function or overactive B cell responses, contribute to the loss of tolerance
• Age is a risk factor, with many autoimmune diseases onset occurring in adulthood
• Microbiome alterations and gut dysbiosis may disrupt immune homeostasis and promote autoimmunity

Autoimmune Diseases

• Type 1 diabetes results from the autoimmune destruction of insulin-producing beta cells in the pancreas
  • Leads to insulin deficiency and hyperglycemia
• Multiple sclerosis (MS) is characterized by autoimmune attacks on the myelin sheath of nerve fibers in the central nervous system
  • Causes neurological symptoms, including vision problems, muscle weakness, and coordination difficulties
• Rheumatoid arthritis (RA) involves autoimmune inflammation of the synovial joints, leading to pain, swelling, and joint damage
  • Autoantibodies (rheumatoid factor, anti-citrullinated protein antibodies) are present in many cases
• Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting multiple organs, including the skin, joints, kidneys, and brain
  • Characterized by the production of autoantibodies against nuclear components (anti-nuclear antibodies)
• Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, involve autoimmune inflammation of the gastrointestinal tract
• Psoriasis is an autoimmune skin disorder characterized by the formation of scaly, itchy patches
• Autoimmune thyroid diseases, including Hashimoto's thyroiditis and Graves' disease, affect the function of the thyroid gland

Diagnosis and Testing

• Autoantibody tests detect the presence of specific autoantibodies in the blood, aiding in the diagnosis of autoimmune diseases
  • Examples include anti-nuclear antibodies (ANA) in SLE, anti-citrullinated protein antibodies (ACPA) in RA, and anti-thyroid peroxidase (TPO) antibodies in Hashimoto's thyroiditis
• Organ-specific functional tests assess the impact of autoimmunity on the affected organs
  • Glucose tolerance tests and insulin levels in type 1 diabetes
  • Thyroid function tests (TSH, T4) in autoimmune thyroid diseases
• Imaging studies visualize the affected organs and detect inflammation or damage
  • Magnetic resonance imaging (MRI) in MS to detect brain and spinal cord lesions
  • Joint radiographs in RA to assess joint damage and erosions
• Biopsy of affected tissues can reveal characteristic histological changes and confirm the diagnosis
  • Skin biopsy in psoriasis shows epidermal hyperplasia and inflammatory infiltrates
• Genetic testing may identify predisposing genetic variants, particularly in familial cases or early-onset disease
• Differential diagnosis is crucial to exclude other conditions with similar clinical presentations

Treatment Approaches

• Immunosuppressive medications are used to dampen the overactive immune response in autoimmune diseases
  • Corticosteroids (prednisone) have broad immunosuppressive effects and are often used as initial therapy
  • Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, slow disease progression in RA and other conditions
• Biologic therapies target specific components of the immune system involved in autoimmunity
  • Monoclonal antibodies against TNF-α (infliximab, adalimumab) are effective in RA, IBD, and psoriasis
  • B cell depletion therapy (rituximab) is used in RA and SLE
• Organ-specific treatments address the consequences of autoimmune damage
  • Insulin replacement therapy in type 1 diabetes
  • Thyroid hormone replacement in Hashimoto's thyroiditis
• Lifestyle modifications, such as diet and stress management, can help manage symptoms and improve overall well-being
• Physical therapy and rehabilitation are important for maintaining function and preventing disability in conditions like MS and RA
• Regular monitoring of disease activity and treatment response is essential to optimize outcomes and minimize side effects

Current Research and Future Directions

• Identifying novel autoantibodies and biomarkers to improve the diagnosis and monitoring of autoimmune diseases
  • Development of antigen-specific assays for early detection and disease stratification
• Investigating the role of the microbiome in the development and progression of autoimmunity
  • Exploring the potential of microbiome-targeted therapies (probiotics, fecal microbiota transplantation)
• Developing antigen-specific immunotherapies to induce tolerance to specific self-antigens
  • Peptide immunotherapy in type 1 diabetes and MS
  • Chimeric antigen receptor (CAR) T cell therapy targeting autoreactive cells
• Advancing personalized medicine approaches based on an individual's genetic and immunological profile
  • Pharmacogenomics to predict treatment response and optimize drug selection
• Exploring the use of stem cell therapies to regenerate damaged tissues and organs
  • Autologous hematopoietic stem cell transplantation in severe autoimmune diseases
• Investigating the role of epigenetic modifications in the development and progression of autoimmunity
  • Targeting epigenetic regulators (histone deacetylase inhibitors, DNA methylation modifiers) as potential therapies
• Conducting large-scale, collaborative studies to unravel the complex interactions between genetic, environmental, and immunological factors in autoimmunity